rs144800506

Variant names:

• chr2-26477447-C-T
• rs144800506
• NM_194248.3:c.2375G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26477447-C-T
• chr2-26477447-C-A
• chr2-26477447-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.2375G>A​(p.Arg792Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000477 in 1,600,004 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R792W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (3 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 3.86
• Publications: 6 publications found

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011497736).
• BP6: Variant 2-26477447-C-T is Benign according to our data. Variant chr2-26477447-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48194.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00164 (249/152188) while in subpopulation AFR AF = 0.00462 (192/41546). AF 95% confidence interval is 0.00409. There are 2 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.2375G>A	p.Arg792Gln	missense	Exon 20 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.134G>A	p.Arg45Gln	missense	Exon 3 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2375G>A	p.Arg792Gln	missense	Exon 20 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.2375G>A	p.Arg792Gln	missense	Exon 20 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.134G>A	p.Arg45Gln	missense	Exon 3 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.134G>A	p.Arg45Gln	missense	Exon 2 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152068 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0161

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000676 AC: 153 AN: 226462 AF XY: 0.000580

Gnomad AFR exome AF: 0.00519

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00126

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.0000528

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00160

GnomAD4 exome AF: 0.000355 AC: 514 AN: 1447816 Hom.: 3 Cov.: 33 AF XY: 0.000346 AC XY: 249 AN XY: 718762

African (AFR) AF: 0.00495 AC: 165 AN: 33300

American (AMR) AF: 0.00121 AC: 52 AN: 42934

Ashkenazi Jewish (ASJ) AF: 0.00112 AC: 29 AN: 25812

East Asian (EAS) AF: 0.000204 AC: 8 AN: 39204

South Asian (SAS) AF: 0.0000359 AC: 3 AN: 83674

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51152

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5728

European-Non Finnish (NFE) AF: 0.000165 AC: 182 AN: 1106108

Other (OTH) AF: 0.00107 AC: 64 AN: 59904

GnomAD4 genome AF: 0.00164 AC: 249 AN: 152188 Hom.: 2 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74402

African (AFR) AF: 0.00462 AC: 192 AN: 41546

American (AMR) AF: 0.00150 AC: 23 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0172 AC: 5 AN: 290

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67986

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.000664 Hom.: 0

Bravo AF: 0.00196

ESP6500AA AF: 0.00484 AC: 21

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000707 AC: 85

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 9 (1)
-	-	1	OTOF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.56
Sift	Benign	0.048	D
Sift4G	Benign	0.067	T
Polyphen		0.64	P
Vest4		0.76
MVP		0.90
MPC		0.25
ClinPred		0.034	T
GERP RS		3.8
Varity_R		0.37
gMVP		0.36
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144800506; hg19: chr2-26700315;